PROJECT SUMMARY/ABSTRACT Recent shifts in practice towards restrictive transfusion strategies in hospitalized patients with anemia have been made without clear and convincing evidence concerning the potential adverse effects on fatigue and functional outcomes. This is important because anemia increases the tendency to become fatigued at any given level of activity (fatigability), increasing fatigue and decreasing activity, which may ultimately impair functional outcomes. Given this, the goals of transfusion may include reducing fatigability, minimizing fatigue and increasing activity, which should be expected to improve functional outcomes. Thus, data on the effects of transfusion on fatigue, activity, and fatigability could inform the design of new transfusion strategies that may improve patient outcomes. One example is symptom-driven transfusion, in which patients would be transfused based on their symptoms, such as fatigue. Therefore, this proposal will 1) provide data for hospitalized patients on the effects of transfusion on fatigue, activity levels, and fatigability, and 2) create and validate a new fatigability instrument that can be used in future studies to measure fatigue, activity, and fatigability in patients, and identify those most likely to benefit from a transfusion. The knowledge acquired through this K23 proposal will fill critical gaps in the understanding of how transfusion affects fatigue as the primary and most significant symptom of anemia, activity as an important clinical outcome, and fatigability as a key mediator of effects on both fatigue and activity. This understanding can improve transfusion practice and ultimately outcomes for hospitalized patients with anemia, by providing evidence that helps clinicians and patients better weigh the potential benefits of transfusion on fatigue, activity, and fatigability, against the risks of unnecessary transfusion during hospitalization. Moreover, this K23 will support additional training in advanced biostatistics and quantitative data analysis, research methodology, and clinical training in the workup, treatment, and management of anemia. These activities, under the guidance and support of a strong mentorship team, will allow me to develop scientifically and professionally, so that at the end of this K23 award period I will be prepared to use the data collected to apply for an RO1 to support an RCT that I would lead as an independent investigator. This planned RCT would build on the data and scientific foundation established as part of this K23, and would compare symptom-driven transfusion to the current practice of uniform restrictive transfusion practice based on Hb alone, using fatigue, activity, and fatigability as outcomes. Therefore, through the training, mentoring, and research experience of this award, I will position myself to become an independent researcher and a leader in how transfusion affects important patient-reported and clinical outcomes in hospitalized patients with anemia. Additionally, I will set myself up to be a leader in the future who studies how new and emerging therapies affect and can improve the health outcomes of hospitalized patients with anemia.